Ultraviolet rays cause inflammation of the skin, resulting in the release of various factors, thereby stimulating melanocytes. Tyrosinase is activated in the stimulated melanocytes to produce melanin. This melanin is delivered to epidermal cells through dendrites extended by melanocytes due to stimulation, thereby melanizing the skin, while the melanin plays a role of absorbing ultraviolet rays to protect the body. However, excess accumulation of melanin causes pigmentation of the skin, such as stains, freckles or the like.
Heretofore, compounds capable of inhibiting a tyrosinase activity of melanocytes have exclusively been developed to inhibit pigmentation of the skin. Known examples thereof include ascorbic acid or derivatives thereof, placental extract, glycyrrhiza extract, hydroquinone or derivatives thereof, kojic acid and the like. Although these ingredients have an action of inhibiting the tyrosinase activity and inhibiting melanogenesis, almost all of them can not exert a sufficient effect because of low activity or causes a problem in safety. Therefore, there has been required the development of an effective and selective melanogenesis inhibitor having an action different from that of tyrosinase activity inhibition.
A method of blocking stimulation to melanocytes has been hitherto known as a technology of inhibiting melanogenesis by an action other than that of tyrosinase activity inhibition. A principal substance that stimulates melanocytes to accelerate melanogenesis in the skin inflamed by ultraviolet rays includes, for example, melanocyte stimulating hormone (MSH), endothelin-1 (ET-1), histamine or the like (see Journal of Cell Science, Vol. 107, page 205, 1994; The Journal of Investigative Dermatology, Vol. 105, page 32, 1995; and Journal of Dermatological Science, Vol. 6, page 146, 1993). Among them, MSH and ET-1 are known to stimulate melanocytes via specific receptors. In particular, inhibition of melanogenesis by means of a method of inhibiting binding to the receptors has been reported for ET-1 (see Pigment Cell Research, Vol. 7, page 373, 1994).
Of course ET-1 is an effective ingredient, however, it is considered to be important to prevent stimulation due to histamine which particularly closely relates to the inflammatory reaction, considering the prevention of pigmentation after inflammation of the skin.
It has commonly been known that histamine is a substance, which is released from mast cells due to various stimulations and has various physiological activities, and includes three specific receptors (H.sub.1, H.sub.2 and H.sub.3). It is considered that an H.sub.1 receptor mainly relates an immediate anaphylactic reaction (allergic reaction), an H.sub.2 receptor mainly relates to secretion of gastric acid, and an H.sub.3 receptor relates to a release or synthesis of histamine in mast cells.
With regard to melanogenesis due to histamine stimulation in melanocytes, however, there was no established theory about the fact whether or not melanogenesis is caused by the reaction via a receptor specific for histamine. Therefore, histamine-mediated melanogenesis has never been made clear. Furthermore, there has hitherto been submitted a report disclosing a whitening effect of an anti-histaminic agent, particularly histamine H.sub.1 receptor antagonist (Japanese Published Unexamined Patent Application No.17115/1990), but the histamine H.sub.1 receptor antagonists do not have an effect of inhibiting melanogenesis as described hereinafter.